POS1468 A HIGH GENETIC RISK OF SLE IS ASSOCIATED WITH AN INCREASED RISK OF MYOCARDIAL INFARCTION AND IMPAIRED KIDNEY FUNCTION; A COMBINED OBSERVATIONAL AND MENDELIAN RANDOMIZATION STUDY
Authors: S. Reid, J. Sandling, P. Pucholt, A. Sayadi, C. Sjowall, M. Frodlund, K. Lerang, A. Jonsen, A. Bengtsson, Ø. Molberg, A. Rudin, S. Rantapää Dahlqvist, L. Ronnblom, D. Leonard
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Cardiovascular morbidity, severe infection and renal damage are amongst the most serious complications of SLE. <h3>Objectives</h3> To combine a mendelian randomization (MR) approach and investigation of a clinical SLE cohort to evaluate the contribution of SLE-genetic risk to the development of myocardial infarction (MI), end-stage renal disease (ESRD) and death from bacterial infections (BI). <h3>Methods</h3> 1487 patients with SLE from Norway and Sweden who fulfilled ≥4 ACR-82 (97%), ACR-97 (98%) or SLICC2012 (94%) classification criteria were included in the study. Clinical data was collected from medical charts and causes of death were retrieved from death certificates. Patients were genotyped using the Global Screening Array or the Immunochip (Illumina). Established, independent SLE risk SNPs (p&lt;5e-8, n=67) were selected and summary statistics for coronary artery disease (CAD) and MI were identified for each SNPs using the MRBase catalog. MR was conducted using the inverse variance weighted method as well as three additional MR methods, on the largest available dataset using a strict definition of MI (ncases=11,622, ncontrols=187,840). The same method was used for analysis of the largest available datasets for dialysis (ncases= 648, ncontrols= 212,841) and BI (ncases= 21,132, ncontrols= 197,660). SNP-manifestation associations from the datasets were used to construct weighted MI/CAD, BI and dialysis PRSs for each patient in the clinical cohort. <h3>Results</h3> The MR analysis revealed a significant association between the genetic risk of SLE and MI (p&lt;0.01). The association was robust to outliers and pleiotropy and consistent across the investigated MR methods. No influence by confounding factors such as hypertension, smoking, alcohol consumption or hyperlipidemia was identified. Individually, 14 SLE SNPs displayed association with MI/CAD and were included in the CAD/MI PRS. In addition, we found an association between the SLE genetic risk and dialysis (p&lt;0.05), whereas the association between SLE genetic risk and BI was not statistically significant (p=0.051). SLE SNPs displaying association with dialysis and BI were included in two separate PRSs. In the clinical cohort, 7.7% of patients had experienced at least one MI, with a mean age at the first event of 60 years. Patients with a CAD/MI PRS in the top quartile displayed a three-fold higher risk of MI (OR 3.04 (1.43−6.49), p&lt;0.01) and a higher risk of ischemic heart disease (MI and/or angina pectoris) (OR 2.64 (1.37−5.11), p&lt;0.01) compared with patients with a CAD/MI PRS in the lowest quartile. In total, 35 % of patients fulfilled the ACR-82 nephritis criterion, and 5.8% had developed ESRD. Patients with a high dialysis PRS displayed a higher risk of nephritis (OR 1.72 (1.15-2.58), p=0.0079), however, a significant association with ESRD could not be demonstrated (OR 1.84 (0.67-5.03), p=0.23). Of the 94 patients in our cohort who were deceased at the time of follow-up, 71 had available death certificates, of which 15 (21%) mentioned infection as a contributing factor. In this data we could not find evidence of an association between a high BI PRS and death from infection (p=0.35). <h3>Conclusion</h3> A high genetic risk of SLE displayed a clear association with MI in the general population, and may also be associated with renal morbidity. Our findings show that combining analysis of large biobank datasets and well-characterized clinical cohorts, may be a useful method for understanding the role of individual SLE risk SNPs in the development of severe SLE sub-phenotypes. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.